We propose to investigate how peripheral immune system cytokines contribute to stress-related alcohol craving and relapse risk in alcohol dependent (AD) individuals with and without high levels of depressive symptomatology. Stress-induced craving in alcoholics is a persistent distress state characterized by elevated negative mood, up-regulated basal adrenal sensitivity and a subsequent dampened arousal response to stress. Notably, this dysregulation is associated with a high susceptibility for relapse, and may be exacerbated in AD individuals with co-morbid depressive and affective symptomology. As chronic stress and alcohol consumption has robust and reciprocal effects on immune system cytokines, we postulate that adaptations in both pro- and anti-inflammatory cytokine levels may contribute to the stress system dysregulation underlying alcohol craving and relapse. Furthermore, that alcohol-related cytokine changes may contribute differentially to the craving state in non-depressed AD individuals compared to those with high co-morbid depressive symptomatology. Our preliminary pilot data shows an increased inflammatory response (high pro-inflammatory cytokines and low anti-inflammatory cytokines) in AD individuals compared with social drinkers (SDs); both at baseline and in response to stress. Moreover, this inflammatory immune system response was shown to be associated with increased stress-induced alcohol craving, negative affect and relapse and was also shown to vary between AD individuals with and without high co-morbid depressive symptomatology. Therefore, our objectives are to investigate the role of pro- and anti- inflammatory cytokine biomarkers in relation to the negative reinforcement processes integral to relapse risk in both non-depressed AD individuals as well as AD individuals with high co-morbid depressive symptomatology (AD+dep VS AD-dep). A 5-year project with a cross-sectional design and a prospective follow-up relapse assessment phase is proposed to study demographically-matched samples of 60 AD (30 +dep / 30 -dep) and 60 SDs (30 +dep / 30 -dep) to address the following specific aims: (1) to examine whether AD subjects and SDs differ with regard to cytokine basal levels and cytokine reactivity following exposure to stress-related imagery. (2) to examine whether AD and SD individuals with and without depressive symptomology will differ with regard to cytokine basal levels and cytokine reactivity following exposure to stress-related imagery. (3) to examine the relationship between stress- induced cytokine adaptations and craving as well as relapse at 14, 30 and 90 days following discharge from inpatient treatment. (4) to explore potential moderators of change in basal and response cytokine levels, including sex and severity of chronic alcohol abuse. As high co-morbid depressive symptomatology is one of the most prevalent psychiatric disorders associated with alcoholism, the identification of new molecular targets for the treatment of alcoholism in both non-depressed individuals as well as those with high depressive symptomatology will be integral to the development of new immune-related, individualized medications for alcohol treatment.